7-[4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy]quinolin-2(1H)-one (brexpiprazole; compound I) is an antidepressant and antipsychotic drug marketed under the brand Rexulti® for the oral treatment of schizophrenia and as an adjunctive treatment to antidepressants in major depressive disorder. REXULTI tablets are intended for oral administration and available in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg strengths. The product was approved in the U.S. in 2015 for the aforementioned indications and is currently in phase III trials for the treatment of agitation associated with Alzheimer's disease and the treatment of PTSD (post-traumatic stress disorder).

Brexpiprazole is an atypical antipsychotic and shows partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.
WO 2006/112464 A1 discloses brexpiprazole and its use for the treatment of schizophrenia and other central nervous system disorders. Brexpiprazole is described in example 1 as a crystalline material obtained as a white powder by recrystallization from ethanol.
WO 2013/162046 A1 characterizes the crystalline brexpiprazole obtained from example 1 of WO 2006/112464 A1 as an “anhydride”, more properly to be understood as an “anhydrate” form of brexpiprazole. Brexpiprazole anhydrate, herein referred to as form I, shows characteristic PXRD reflections at 2 Theta angles of 14.4°, 19.1°, 20.2°, 21.3° and 23.2°. WO 2013/162046 A1 also discloses a crystalline hydrate of brexpiprazole which is characterized by means of PXRD. Brexpiprazole hydrate is described as showing characteristic PXRD reflections at 2 Theta angles of 7.7°, 9.4°, 11.8°, 18.9° and 24.0°. WO 2013/162046 A1 also discloses a crystalline dihydrate of brexpiprazole which is characterized by means of PXRD, Infrared spectroscopy, Raman-spectroscopy, and 1H-NMR. Brexpiprazole dihydrate is described as showing characteristic PXRD reflections at 2 Theta angles of 8.1°, 8.9°, 15.1°, 15.6° and 24.4°. An advantage of brexpiprazole dihydrate is described to be that when injected intramuscularly into rats, the dihydrate crystals can still be detected at the injection site, while the anhydrate form (form I) was no longer detectable 56 days after the injection. The brexpiprazole dihydrate crystals are thus suggested for injectable preparations of brexpiprazole with sustained release properties.
WO 2013/161830 A1 discloses an aqueous suspension comprising secondary particles formed by aggregation of brexpiprazole having a mean secondary particle diameter of 1 to 50 μm. A bulk powder is to be produced wherein brexpiprazole dihydrate should have a defined primary particle size. Milling and grinding are mentioned as methods for the preparation of the bulk powder.
Size reduction processes can expose the processed material to dry conditions and/or to elevated temperatures. A learning from WO 2013/162046 A1 is that the suitability of brexpiprazole for pharmaceutical preparations with sustained release properties is dependent on brexpiprazole being present as brexpiprazole dihydrate. The presence of a solid form which disappears more quickly than the dihydrate when applied intramuscularly could even compromise the desired delayed release effect, as a part of brexpiprazole would then dissolve more quickly upon intramuscular injection, leading to an undesired early peak in the brexpiprazole blood level.